rs182700746

Variant names:

• chr1-6424818-C-T
• rs182700746
• NM_031475.3:c.-138C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031475.3(ESPN):​c.-138C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 883,224 control chromosomes in the GnomAD database, including 1,392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (398 hom., cov: 33)
  • Exomes 𝑓: 0.045 (994 hom.)
• Consequence: ESPN NM_031475.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.11
• Publications: 1 publications found

Genes affected

ESPN (HGNC:13281): (espin) This gene encodes a multifunctional actin-bundling protein. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells. Mutations in this gene are associated with autosomal recessive neurosensory deafness, and autosomal dominant sensorineural deafness without vestibular involvement. [provided by RefSeq, Nov 2009]

HES2 (HGNC:16005): (hes family bHLH transcription factor 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in anterior/posterior pattern specification; regulation of neurogenesis; and regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-6424818-C-T is Benign according to our data. Variant chr1-6424818-C-T is described in ClinVar as Benign. ClinVar VariationId is 1275204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	NM_031475.3	MANE Select	c.-138C>T		5_prime_UTR	Exon 1 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.-138C>T		5_prime_UTR	Exon 1 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.-138C>T		5_prime_UTR	Exon 1 of 14	NP_001354402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	ENST00000645284.1	MANE Select	c.-138C>T		5_prime_UTR	Exon 1 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000636330.1	TSL:5	c.-138C>T		5_prime_UTR	Exon 1 of 11	ENSP00000490186.1	A0A1B0GUN9
	HES2	ENST00000377837.5	TSL:1	c.-364G>A		upstream_gene	N/A	ENSP00000367068.1	Q9Y543-2

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9646 AN: 151344 Hom.: 398 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.0774

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0643

Gnomad FIN AF: 0.0347

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0392

Gnomad OTH AF: 0.0687

GnomAD4 exome AF: 0.0451 AC: 33017 AN: 731772 Hom.: 994 Cov.: 9 AF XY: 0.0454 AC XY: 16143 AN XY: 355680

African (AFR) AF: 0.106 AC: 1547 AN: 14600

American (AMR) AF: 0.0455 AC: 314 AN: 6894

Ashkenazi Jewish (ASJ) AF: 0.0864 AC: 962 AN: 11132

East Asian (EAS) AF: 0.165 AC: 3615 AN: 21934

South Asian (SAS) AF: 0.0528 AC: 1073 AN: 20326

European-Finnish (FIN) AF: 0.0277 AC: 624 AN: 22508

Middle Eastern (MID) AF: 0.0974 AC: 214 AN: 2198

European-Non Finnish (NFE) AF: 0.0382 AC: 22975 AN: 600886

Other (OTH) AF: 0.0541 AC: 1693 AN: 31294

GnomAD4 genome AF: 0.0638 AC: 9656 AN: 151452 Hom.: 398 Cov.: 33 AF XY: 0.0640 AC XY: 4733 AN XY: 73994

African (AFR) AF: 0.102 AC: 4219 AN: 41434

American (AMR) AF: 0.0558 AC: 848 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.0774 AC: 268 AN: 3464

East Asian (EAS) AF: 0.143 AC: 731 AN: 5126

South Asian (SAS) AF: 0.0650 AC: 314 AN: 4830

European-Finnish (FIN) AF: 0.0347 AC: 357 AN: 10302

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0392 AC: 2655 AN: 67784

Other (OTH) AF: 0.0699 AC: 147 AN: 2104

Alfa AF: 0.0522 Hom.: 41

Bravo AF: 0.0682

Asia WGS AF: 0.0890 AC: 296 AN: 3348

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		1.1
PromoterAI		-0.029	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs182700746; hg19: chr1-6484878; COSMIC: COSV105308072; COSMIC: COSV105308072;